Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
The type I interferon alpha (IFN-α) family of proteins exhibit clinically important antiviral, antiproliferative and immunomodulatory activities, and various IFN-α, proteins have been approved for treating a variety of diseases, including hepatitis and cancers. Due to the short plasma half-life of the originally approved IFN-α proteins, longer-acting versions have been developed: in particular, peginterferon alfa-2a, marketed by Hoffman-La Roche (Nutley, N.J.) under the trade name PEGASYS®; peginterferon alfa-2b, marketed by Schering-Plough (Kenilworth, N.J.) under the trade name PegIntron®; and Albuferong, a fusion between human serum albumin and interferon alpha-2b, which is in late-stage clinical development by Human Genome Sciences.
IFN-α proteins affect a variety of cellular functions, including DNA replication and RNA and protein synthesis, in both normal and abnormal cells. Thus, cytotoxic effects of IFN-α therapy are not restricted to tumor or virus infected cells but are also manifested in normal, healthy cells as well. As a result, undesirable, but typically reversible, side effects arise during IFN-α therapy, particularly when high doses are required to achieve a therapeutic effect. For example, administration of IFN-α proteins can lead to reduced red blood cell, white blood cell and platelet counts, and high doses commonly produce flu-like symptoms (e.g., fever, fatigue, headaches and chills), gastrointestinal disorders (e.g., anorexia, nausea and diarrhea), mood changes and alteration of liver enzymes.
Such side effects can be particularly of concern due to the long treatment times typically required with IFN-α-based therapy. For example, the recommended duration of peginterferon alfa/ribavirin combination therapy for hepatitis C virus (HCV) infection is between 24 and 48 weeks, depending on HCV genotype and baseline viral load. The treatment duration for certain cancer indications may be even longer, as evidenced by a recently completed clinical trial of peginterferon alfa-2b as adjuvant therapy for resected stage III melanoma, in which the patients were treated with 6 μg/kg peginterferon alfa-2b a week subcutaneously for 8 weeks (induction phase), followed by 3 μg/kg per week subcutaneously for an intended treatment duration of 5 years (maintenance phase) (Eggermont A. M. M. et al., Lancet 372:117-126 [2008]).
In addition to the potential for problematic side effects, the therapeutic effect of IFN-α therapy cay vary widely among patients with a particular disease. For example, combination peginterleron alfa-2b/ribavirin therapy for HCV produces a sustained viral response (SVR) rate of between approximately 20% and 93% in various patient groups defined by HCV genotype and baseline viral load. Also, HCV patients of African ancestry have significantly lower sustained viral response (SVR) rates than patients of European ancestry. See, e.g., McCone, et al., Hepatology 48(4):430A-431A, Abstr. No. 268 (59th Ann. Mtg. Am. Assoc. Study Liver Dis., AASLD, San Francisco, Calif., USA, Oct. 31-Nov. 4, 2008); Reid, A. E., Curr. Hepatitis Rep., Vol. 7, No. 3, pp. 120-126 (2008); Jacobson, I. M. et al. Hepatology 46 (4): 971-981 (2007). Similarly, Eggermont et al., supra, reported better clinical outcomes for patients with earlier stage III melanoma than for patients with later stage disease, in particular an overall risk reduction of relapse of approximately 18-25%.
Thus, in view of the side effect and variable response and sensitivity profiles observed with IFN-α therapy, a need exists for a way of identifying patients who are most likely to benefit from IFN-α therapy. The present invention addresses this need.